A wide variety of insulin formulations are currently marketed in order to provide the diabetic patient convenience and flexibility in treating diabetes. The ultimate goal is to achieve near normal glycemic control and thereby minimize the complications associated with diabetes. A number of significant advances have been made in this area including the development of formulations with different pharmacokinetics after subcutaneous injection. These formulations include Regular insulin, semi-Lente insulin, globin insulin, isophane insulin, insulin zinc suspension, protamine zinc insulin, and Ultralente insulin. These formulations can be generally classified as short, intermediate, or long acting.
None of these commercially available insulin formulations alone can provide normal glycemic control for the diabetic patient. Therefore, in addition to dietary control and proper glucose monitoring, a typical treatment regimen requires using a combination of insulin formulations. The most common subcutaneous regimen involves twice-daily injection of mixtures of short and intermediate acting insulin. Galloway, J. A. & Bressler, R., Med. Clin. North Am., 62, 663-680 (1978). Patients routinely prepare mixtures of desired ratios in an extemporaneous fashion by drawing up in a single syringe appropriate volumes from vials of short and intermediate acting insulin. Mixture formulations of short and intermediate acting insulin are currently marketed in a number of fixed ratios. These products offer the patient convenience and better precision over day to day manual mixing.
Mixtures containing a combination of soluble, short acting insulin and a suspension of Neutral Protamine Hagedorn (NPH) are widely marketed because the two formulation types are compatible and have sufficient shelf and in-use stability. JENS BRANGE, GALENICS OF INSULIN (Springer-Verlag 1987). Biphasic preparations, mixtures of crystalline bovine insulin and soluble porcine insulin, have also been prepared. Due to the low solubility of the bovine insulin, these mixtures contain only a small amount of bovine insulin in the soluble phase. Mixed bovine and porcine mixtures of NPH insulin have not been successfully prepared due to physical instability arising from an equilibrium exchange between the dissolved insulin and the solid phase. Id. Other mixtures of short and long acting (Ultralente) formulations cannot be prepared because of significant long-term stability issues arising from incompatibility of the formulations, particularly if a zinc binding buffering agent, such as a phosphate buffer is utilized in the formulation. Most significantly, there are no examples of suspension-type fixed insulin mixture preparations of insulin-NPH and regular insulin currently marketed where two different insulin proteins are combined together.
Most recently, monomeric insulin analogs have been developed that have an ultra rapid time action profile. These monomeric analogs possess a much more rapid onset of activity than regular insulin. The preparation of various monomeric analogs is disclosed in U.S. patent application number 07/388,201 (Chance et al., EPO publication number 383 472), and Brange et al., EPO publication number 214 826. Preparing mixtures containing a rapid-acting insulin analog and NPH insulin is particularly advantageous because the properties of monomeric analogs are considered greatly superior to those of regular insulin. Therefore, mixtures of the monomeric insulin analog and insulin-NPH provide for an immediate reduction in glucose levels and a intermediate acting basal effect.
Unlike regular insulin and insulin-NPH formulation mixtures, mixtures of the monomeric insulin analog and insulin-NPH are heterogeneous. That is, the active protein is different in the NPH crystals and in the solution. In a heterogeneous formulation, any equilibrium exchange that occurs between the non-uniform product i.e., solid and soluble phases, is undesirable. If equilibrium exchange occurs, the heterogeneous formulation fails to maintain the defined ratio of the monomeric insulin in the soluble phase and the insulin in the solid phase over a sufficient shelf-life. That is, if the monomeric analog aggregates with the protamine, the rapid time action would be compromised. Similarly, if the insulin in the solid phase dissolves into the soluble phase, the desired time action profile is altered.
The present invention provides a parenteral formulation comprising a monomeric insulin analog and insulin-NPH. The invention further provides specific conditions under which the formulation is stable for an extended period and, thus suitable for commercial development. The formulations of the present invention permit the diabetic to control more accurately glucose levels thereby delaying or eliminating the onset of various diabetic complications. Quite remarkably, the preferred formulations of the present invention demonstrate extended stability; that is, the equilibrium exchange between the crystalline and soluble proteins is minimized. Accordingly, the formulations are suitable for commercial application.